1. Field of the Invention
The present invention relates to an improved method for the synthesis of desferrioxamine B and analogs and homologs thereof.
2. Description of the Prior Art
The microbial iron chelator, siderophore, desferrioxamine B [N-(5-(3-((5-aminopentyl)hydroxycarbamoyl)propionamido)pentyl)-3-((5-(N-hy droxyacetamido)pentyl)carbamoyl)-propionohydroxamic acid] was isolated from Streptomyces pilosus and characterized by Bickel [Helv. Chim. Acta., Vol. 43, p. 2129] in 1960. It is a linear trihydroxamate ligand which forms a very stable hexacoordinate, octahedral [Modell et al, The Clinical Approach to Thalassaemia, Grune and Stratton, London, pp. 217-241 (1984)] complex with Fe(III), Kf=1.times.10.sup.30 M.sup.-1. The ligand employs its three bidentate hydroxamates units in chelating metal ions.
Although desferrioxamine B will bind a number of different +3 cations, e.g., Al(III), Ga(III), Cr(III), it exhibits a high specificity for Fe(III), and is utilized by Streptomyces pilosus for the acquisition of iron from the environment. Because of the ligand's metal selectivity and low toxicity it has been employed in the treatment of several iron overload diseases, e.g., thalassaemia [Development of Iron Chelators for Clinical Use (Martell et al, Eds.) Elsevier/North Holland, New York (1981)]. However, desferrioxamine B does not offer a completely satisfactory solution to the iron overload problem. The drug is cleared by the kidneys and has a very short half-life in the body, and thus the patient must be maintained on constant infusion therapy. It is not orally effective. Because of these shortcomings, investigators have explored the potential of other ligands as therapeutic iron chelators. To date these investigations have not included modification of the desferrioxamine molecule simply because of the lack of high yield or facile approaches to the synthesis of the molecule.
Desferrioxamine B was first synthesized in 1962 by Prelog et al [Helv. Chim. Acta., Vol. 75, p. 631 (1962)]. However, because of the number of steps in the synthesis and the low yield of the sequence, the method does not enable the production of large quantities of the chelator or its analogs. A retrosynthetic analysis of the ligand reveals that the desferrioxamine molecule is made up of two fundamental units, 1-amino-5(N-hydroxyamino)-pentane and succinic acid. The key to its synthesis is the production of this amino-hydroxyaminopentane unit and its condensation with succinic acid. Prelog approached this problem beginning with the starting material 1-amino-5-nitropentane, an amine which was accessible in only 46% yield [Bickel et al, Helv. Chim. Acta., Vol. 43, p. 901 (1960)]. This compound was next N-carbobenzoxylated and the terminal nitro group reduced to the corresponding hydroxyamino group. This key intermediate was condensed with succinic acid followed by a series of other dicyclohexylcarbodiimide catalyzed acylations along with several reductions to produce desferrioxamine B. The overall yield of this eleven step sequence was 6%.
It is an object of the present invention to provide novel, improved high yield methods for the production of desferrioxamine B and homologs and analogs thereof.